Project Summary: Efforts at understanding the neurobiological correlates of traumatic brain injury (TBI), prefrontal function and suicidal ideation have thus far provided inconclusive results. Primary blast-related TBI is common in returning veterans and appears to produce neurophysiological changes that resemble diffuse axonal injury (DAI). Disruptions in brain neural circuits that support cognitive processing in individuals with TBI may result in deficits in executive function including reduced problem solving and decision-making capacity. Moreover, veterans with TBI are often co-morbid for substance abuse and it has been shown that use of alcohol and illicit drugs can further compromise executive mediated functions known to depend on the frontal cortex. It has been proposed that these functional deficits may lead to cognitive rigidity and psychological distress and thus may serve as markers for suicidal risk. The proposed research builds on existing neurobiologic models of frontal function and will extend our understanding of TBI related brain changes by applying functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) techniques. Accordingly, we will examine blood oxygen level dependent (BOLD) signal changes within the cingulate and dorsolateral prefrontal cortices as well as the amygdala in TBI subjects, with and without a history of substance abuse, to characterize the nature of these patterns of signal change (higher/lower) in relation to healthy control subjects. We will determine whether measures of white matter microstructure, as measured by DTI methods, are abnormal in TBI subjects, with and without a history of substance abuse compared with healthy control subjects. We will also examine the relationship between BOLD signal changes and reduced FA values and suicidal ideation. Lastly, we will test the hypothesis that reduced FA and reduced activation in frontal regions in both substance abusing and non- substance abusing TBI veteran groups is significantly correlated with suicidal ideation, and that the correlation will be stronger for the TBI plus substance abuse cohort. We believe the proposed studies will impact veteran's health by providing important insights into the neurobiological correlates of suicide and TBI that may lead to new approaches for identification and treatment of behavioral consequences of TBI. PUBLIC HEALTH RELEVANCE: Narrative: Traumatic brain injury (TBI) is an important medical problem for active combat veterans. The return of veterans from Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF), many of whom have suffered mild TBI, has emphasized the crucial importance of understanding the neurobiologic and neuropsychological consequences of this type of brain injury. Furthermore, several studies point to the urgent need to define the neurobiological and cognitive underpinnings of suicidal ideation and behavior in veterans with TBI with and without comorbid substance abuse/dependence disorders. The evaluation of the neurophysiologic and cognitive predictors of suicide risk and recovery are needed to improve treatments. We believe the proposed studies will impact veteran's health by providing important insights into the neurobiological correlates of suicide that may lead to new approaches for identification and treatment of behavioral consequences of TBI.